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Molecular hydrogen therapy

From EverybodyWiki Bios & Wiki


Molecular hydrogen therapy is the hypothesis that hydrogen gas can have a therapeutic effect on animals or humans. Molecular hydrogen (H2) has characteristics of a therapeutic drug; it can penetrate membranes, including the blood brain barrier,[1][2][3] and rapidly diffuse into the cytosol, mitochondria and nucleus. Its ability to diffuse into the mitochondria and the nucleus are of particular interest because these organelles are difficult to target pharmacologically and are the primary site for generation of reactive oxygen species (ROS).[3] Accumulation of ROS can cause oxidative damage of macro-biomolecules such as DNA. Molecular hydrogen can prevent oxidative damage without interfering with other cellular processes[2] giving it anti-oxidant properties.[3][4]

Molecular hydrogen also exhibits anti-inflammatory, anti-allergic, and anti-apoptotic properties.[3][5] As an anti-inflammatory agent, molecular hydrogen can down-regulate various pro-inflammatory cytokines in the cells of the injured tissues.[6] As an anti-allergic agent, molecular hydrogen can decrease the activity of the Ca2+ signalling pathway which controls the expression of certain genes involved in immediate allergic reaction.[5] As an anti-apoptotic agent, molecular hydrogen can be consumed to prevent strokes and ischemia-reperfusion injury since it can inhibit the activation of caspase-3 in intracranial neurons.[3][6] Molecular hydrogen can also be used in post-operation therapy to prevent ischemia-reperfusion injury according to a 2015 study with rats and the effects of hydrogen-rich saline after pancreas transplantation.[7]

Available Forms

Inhalation

Hydrogen gas can be administered via inhalation using facemasks, ventilators, gas chambers or nasal cannulas. A 2-4% hydrogen gas mixture is commonly administered since it is below the flammability level at those concentrations.[8]

Injection

Hydrogen gas can also be administered via intravenous injection as hydrogen-rich saline[1][2][3] since molecular hydrogen in hydrogen-rich water evaporates over time and is also lost in the stomach, intestines and expelled out the lungs.[3] Hydrogen-rich saline is generated by dissolving hydrogen into normal saline under high pressures.[1]

Ingestion

Hydrogen gas can be ingested as hydrogen-rich water. Hydrogen gas solubilized in water is referred to as hydrogen-rich water and can be produced by: dissolving hydrogen gas into water under high pressure, reacting water with metals such as magnesium, or via electrolysis.[1][3]

Specific Populations

In Pre-Natal Period

Hypoxia-ischemia

In animal models, it has been shown that inhalation of molecular hydrogen (H2) and injection of hydrogen-rich saline can protect the brain from hypoxia-ischemia insult during the pre-natal period. Hypoxia-Ischemia, a major cause of severe brain damage in newborns, is due to intracranial neuronal cell death via apoptosis.[6] Neuronal apoptosis which can be initiated by increased inflammation and oxidative stress after ischemic brain injury can be treated for with hydrogen-rich saline.[6] Molecular hydrogen inhibits neural apoptosis by targeting reactive oxygen species (ROS) that cause oxidative stress. Reduction in ROS in turn reduces oxidative damage to DNA, lipids and proteins of the neuronal cell and therefore prevents the activation of caspase-3,[6] a protein involved in the apoptosis signalling pathway. Since the neonatal brain is more susceptible to oxidative damage and there is no known detoxification system for excessive ROS, administration of molecular hydrogen can be effective in preventing neuronal cell apoptosis.[9]

In Adults

Smoking

Consumption of hydrogen-rich water has been shown to be beneficial for smokers according to an open label pilot study conducted in 2010. The study reported a statistically significant and clinically effective decrease in total cholesterol/HDL (high density lipoproteins) ratio from baseline to week 4 showing that relief from oxidative stress was most significant among smokers.[10]

Type II Diabetes

As per a human study conducted in 2008, hydrogen-rich water also seems to improve lipid and glucose metabolism in individuals with type II diabetes mellitus and impaired glucose tolerance. Therefore hydrogen-rich water may have a beneficial role for diabetes and insulin resistance.[11]

Cancer

Oxidative stress has been regarded as a major contributor to the development of hepatic cancer.[12] A study published in 2011 on the protective role of hydrogen-rich saline proposed the existence of a casual link between reactive oxygen species (ROS) and cancer.[12] ROS are usually increased in oncogene activation and are involved in the progression and metastasis of cancers.[13] Since studies have shown that molecular hydrogen can neutralize free radicals in all types of cells,[14] hydrogen might be a therapeutic gas for cancer by eliminating the toxic ROS that are generated through radiotherapy.[13] A study published in "Science" investigated the possibility of hyperbaric hydrogen serving as a novel therapy for skin cancer. Tumor-bearing mice were treated to a 97.5% hydrogen-2.5% oxygen gas mixture at a pressure of 8 atmospheres for 2 week periods. It was found that the tumors regressed suggesting that molecular hydrogen might prove to be a novel therapy against tumors.[14]

Depression

Previous animal and clinical studies have shown that at the molecular symptoms of depression include a significant increase in oxidative stress biomarkers, such as reactive oxygen species (ROS), in the central nervous system.[15] Oxidative stress is the result of excessive ROS build-up which can be prevented with the help of antioxidants, as per the findings of a 2014 study on antioxidants as a candidate treatment for depression.[16] Molecular hydrogen has been shown to selectively reduce ROS and therefore serve as a novel anti-oxidant with no known side effects. A 2016 study investigated the effects of hydrogen-rich water on depressive-like behaviour in mice.[15] The study showed that chronic stress induced the production of ROS in the central nervous system which plays an important role in the release of neurotransmitters involved depression. However, mice that were given hydrogen-rich water exhibited a decrease in ROS in areas of the brain such as the hippocampus and cortex suggesting that hydrogen-rich water may be used as a novel, effective intervention of depression. This can be further verified by replicating the same study in a clinical setting in the future.[15]

Sports Medicine

Accumulation of excess reactive oxygen species (ROS) in skeletal muscles are one of the many by-products of intense exertion during exercise. This results in oxidative stress in the muscles and can lead to muscle weakness, muscle fatigue, micro-injury and inflammation.[17] Many studies on the effects of hydrogen-rich water or hydrogen-rich saline on oxidative stress induced by intense exertion during exercise have been conducted. In a 2012 pilot study,[17] the efficacy of hydrogen-rich water post-exercise was investigated. Ten male soccer players, aged 20.9 ± 1.3 years old were involved in the study, all of whom were non-smokers and not taking any supplements or medications. Each subject was examined twice, given either hydrogen-water or placebo-water. Hydrogen-water was generated by placing a plastic shelled product consisting of 99.9% pure metallic magnesium in drinking water via the chemical reaction: Mg + 2H2O → Mg (OH)2 + H2. The placebo-water was generated by placing the empty plastic shell in drinking water 24 hours prior to drinking. In addition, the quantity of water and time of consumption was standardized among participants. Subjects were provided with three 500 mL of drinking water and were instructed to drink one bottle at 10pm the day before the test, and one at 5am and one at 6:20am the day of the examination. The examination consisted of 3 tests: 1) maximal oxygen uptake (VO2max), 2) exercise for 30min at 75% VO2max, 3) Running. Blood samples were taken before and after tests 2 and 3. The blood samples were used to measure the concentration of reactive oxidative metabolites (dROMs), biological antioxidant power (BAP) and creatine kinase (CK). It was noticed that 45 and 60minutes after exercise, their concentrations were significantly lower in the hydrogen-water group than in the placebo-water group. This suggests that hydration with hydrogen-water can prevent the adverse effects associated with intense exercise.[citation needed]

In Elderly

Alzheimer's Disease

Alzheimer's disease, is the most common neurodegenerative disease that progressively leads to dementia and affects about 5% of individuals 65 years or older. Medications that target the underlying pathogenic mechanisms of neurons such as oxidative stress and amyloid cascade.[18] In particular, accumulation of amyloid β-42, a protein of the neuronal cell membrane initiates a cascade of events that results in oxidative stress.[19][20] Oxidative stress increases with age due to increase in accumulation and decrease in elimination of reactive oxygen species (ROS). It is claimed that when this imbalance occurs in the brain it damages the DNA and proteins of neuronal cells resulting leading to Alzheimer's disease.[20] A 2010 study in a rat model reported that hydrogen-rich saline reduced amyloid cascade induced oxidative stress and improved memory functions.[18]

Parkinson's Disease

Damaged mitochondria in neuronal cells resulting in excess reactive oxygen species (ROS) leads to oxidative stress. Parkinson's disease is the second most common neurodegenerative disorder after Alzheimer's disease that affects more than 1% of individuals 60 years or older.[21] Parkinson's disease is a progressively chronic condition that results in loss of controlled movement and although medications for symptom relief[22] such as levodopa[23] are available, there is no known cure for Parkinson's disease.[22] However, in a 2009 mouse study[24] it was found that mice that were drinking hydrogen-rich water exhibited a decrease in accumulation of DNA damage and lipid peroxidation due to oxidative stress showcasing that hydrogen-rich water may be able to slow down the progression of Parkinson's disease.[3][24]

A 2013 randomized double-blind clinical pilot study on the effects of hydrogen therapy in Parkinson's disease showed that drinking hydrogen-rich water reduced oxidative stress and improved the symptoms of Parkinson's disease in patients.[25] The effects of hydrogen-rich water observed in this study among agreed with previous findings observed in animal models. However, the mechanism by which molecular hydrogen reduces oxidative stress in the brain after the consumption of hydrogen-rich water is still unknown.[25]

Another 2016 human study showed that intake of hydrogen-rich water reduces neurotoxic damage.[23] The clinical study was set up as a randomized double-blind placebo-controlled multi-center trial and organized by the Department of Neurology at Juntendo University School of Medicine in accordance with consolidated Standards of Reporting Trials guideline. 14 hospitals were involved as trial centers and the study was advertised therefore, the patients were participating voluntarily. These patient volunteers were included in the study if they were diagnosed with Parkinson's disease according to the United Kingdom Brain Bank criteria and outpatients were preferred over admitted patients. Participants in controlled group were required to drink 1L of hydrogen-rich water and those in the placebo group were required to drink normal water. In addition, participants in both groups were encouraged to continue with their prescription of levodopa during the 72-week trial. One of the major challenges in this study was that some participants found it difficult to consume 1L of water daily. Nonetheless, this study showcased that the daily consumption of 1L of hydrogen-rich water exhibited no adverse side effects, especially in patients who continued to take levodopa during the study.[23]

Aging

Exposure to ultraviolet radiation (UVA, UVB) increases reactive oxygen species (ROS) formation. This also reduces the formation of type-I collagen which is a symptom of photo-aging skin at the molecular level leading to the formation of skin wrinkles.[26] A 2012 study showed that consumption of hydrogen-rich warm water is effective in reducing oxidative stress without side effects.[26] The anti-oxidant response of hydrogen-rich water reduce the increased levels of ROS due to UVA and UVB, inhibit cell death and DNA damage which in turn prevents the disruption of type-I collagen production. Therefore, hydrogen-rich water has the potential to be an anti-aging therapy for daily skin care by repressing UV-induced skin damage since hydrogen has selective-ROS-scavenging properties. Continuous use of hydrogen-rich water reduces oxidative stress in the skin and is expected to prevent wrinkle formation.[citation needed]

Contraindication

There is currently no known contraindication for molecular hydrogen therapy however, the following are some precautions and notes on use.[citation needed]

Inhalation of hydrogen gas using facemasks can be challenging for neurologically impaired individuals due to the inconsistency in inhalation; nonetheless, it is still effective therapy for neurological diseases.[1] In addition, a safe concentration of pure hydrogen gas in air is <4% since it is inflammable beyond this threshold.[6]

It is also noteworthy that unlike some anti-oxidant supplements, molecular hydrogen does not disturb metabolic oxidation-reduction reactions or the functioning of other reactive oxygen species (ROS) involved in important cell signaling pathways.[2]

As of February 2010, a clinical study on the effects of molecular hydrogen (H2) therapy on subjects who are pregnant, breast-feeding or planning on becoming pregnant has yet to be conducted.[10]

Side Effects

Regardless of which form it is administered in (gas, water, saline), molecular hydrogen therapy should not have serious side effects since it selectively neutralizes hydroxyl radicals (OH●), the strongest oxidant of the reactive oxygen species (ROS) family.[2] In addition, molecular hydrogen does not eliminate the ROS generated by macrophages and neutrophils (white blood cells) of the innate immune system in order to fight bacterial infections.[3]

Still, in 2010, a human clinical study was conducted using hydrogen-rich water to confirm the absence of major side effects in molecular hydrogen therapy.[10] The open label pilot study involved 10 males and 10 females over the age of 40 who were did not have uncontrolled hypertension, Type I or Type II diabetes, cardiovascular disease, cancer, renal disease, liver disease, psychiatric disorders, and history of drug/alcohol abuse.[10] Subjects were asked to consume a minimum of 1.5L of hydrogen rich water at specified times of the day. However, laboratory tests for routine health markers reviled small changes in their levels which was not physiologically significant because they remained within acceptable clinical range.[10] This means that the consumption of hydrogen-rich water did not alter the overall health of the subjects.

Within the same study, side effects were experienced by 13 of the 20 subjects (65.0%). 3 subjects reported loose stools and 1 subject reported an increase in frequency of bowel movement, 1 subject reported heartburn and 1 subject reported headache. Of the 20 subjects, 4 subjects (20.0%) experienced adverse side effects that were investigated as having a possible relationship to the test.[10]

In general, molecular hydrogen has been demonstrated safe for consumption in Hydreliox, a breathing gas mixture of 49% hydrogen, 50% helium and 1% oxygen. Hydreliox breathing gas is used to prevent decompression sickness and nitrogen narcosis among deep sea divers.[3]

Interactions

In a 2010 human study involving the effectiveness of hydrogen-rich water, it was noticed that alcohol and meat consumption led to an increase in gamma glutamyl transferase (GGT) levels in a dose dependant manner. GGT is an enzyme, a routine health marker for oxidative stress, and is widely distributed in the human body.[10] Laboratory tests for routine health markers reviled a statistically significant increase in GGT in the group that was consuming hydrogen-rich water. However, these changes were not considered physiologically significant because they remained within acceptable clinical range.[10] This implies that alcohol and meat consumption leads to an increase in oxidative stress levels in the body therefore requiring the consumption of hydrogen-rich water in higher doses. Unfortunately, since subjects were not required to maintain food records the notion that increases in GGT levels were related to these factors could not be confirmed.[10]

Pharmacology

Mechanism of Action

As of July 2016, there is no evidence that the human body has a mechanism to produce molecular hydrogen (H2). However, molecular hydrogen is produced by anaerobic bacteria in the large intestine during fermentation of non-digestible carbohydrates.[3] Since the use of antibiotics can alter the population of these bacteria, it can also alter the amount of molecular hydrogen produced. Regardless, of the population of these bacteria, majority of the molecular hydrogen produced by them diffuses into the circulatory system and is lost through the lungs during exhalation of air. Some of it is metabolized by colonic microbiota and some is eliminated by flatus.[3] In addition, the amount of free molecular hydrogen in the earth's atmosphere is very little[3] and therefore, not enough to help relieve oxidative stress in cells through inhalation of air.

Oxidative stress is caused by the accumulation of reactive oxygen species (ROS) which can be caused by inflammation due to injury, intense exercise, heart attack, tissue damage due to cessation of blood flow, organ transplants,[2] diabetes, hypertension,[11] atherosclerosis[11] and cellular processes, such as the production of ATP in the mitochondria.[2]

Most often, ROS are the result of electron leakage in the electron transport chain and the Krebs cycle, both of which take place in the mitochondria of a cell. Superoxide anion radicals (O2-●), a type of ROS in the mitochondria, are converted into hydrogen peroxide (H2O2) with the help of an enzyme called superoxide dismutase. Hydrogen peroxide is further degraded into water by another enzyme called glutathione peroxidase.[2] In the presence of excess superoxide anion radicals, transition metal ions such as iron (Fe3+) and copper (Cu2+) are reduced which then react with hydrogen peroxide to hydroxyl radicals (OH●) by the Fenton reaction.[2]

Hydroxyl radicals are the most harmful of the ROS and cause irreversible damage to all macro-biomolecules including DNA,[4][27] proteins[4] and lipids.[10] Hydroxyl radicals can cause DNA fragmentation.[27] Hydroxyl radicals can also cause oxidative damage to proteins[4] and if the affected protein happens to be a DNA repair protein then the damage to both DNA and protein can be irreversible. Hydroxyl radicals also cause lipid peroxidation, oxidation of unsaturated fatty acids, causing damage to cell membranes.[10]

Molecular hydrogen has been proven to function as a scavenger and neutralizer of hydroxyl radicals; therefore, its consumption can relieve oxidative stress.[2] As of May 2016, the existence of enzymatic hydroxyl radical detoxification reaction(s) is still not known[8][28] and there are no naturally occurring mechanisms to prevent the effects of the hydroxyl radical.[1]

Gene Regulation

File:A model of the proposed pathway.jpg
When free radical chain oxidation generates oxidized phospholipid mediators, Ca2+ signaling is induced, followed by the activation of calcineurin and subsequent induction of the NFAT pathway. On the other hand, H2 modifies the production of oxidized phospholipids by modulating free radical chain reactions. The putative oxidized phospholipids appear to function as antagonists and lead to a decline in Ca2+ signaling.[citation needed]

A 2016 study using cell cultures,[5] showed that molecular hydrogen can regulate the Ca2+ signal transduction pathway which is involved in the expression of many genes. This study showed that that administration of as little as 1% molecular hydrogen at normal body temperature (37°C) can prevent hydroxyl radicals from triggering free-radical chain reactions and ultimately decreasing Ca2+ signalling. This is important because free-radical chain reactions target unsaturated fatty acids of bio-membranes leading to lipid peroxidation, resulting in oxidized phospholipid species. Oxidized phospholipids activate transcription factors involved in Ca2+ signal transduction pathway. These transcription factors upregulate the expression of certain genes such as the tumor necrosis factor (TNF)-α gene.[5] The tumor necrosis factor (TNF)-α gene encodes for a pro-inflammatory cytokine (protein) mainly secreted by macrophages (white blood cells) that is also a potent cytotoxin. The protein is involved in regulating cell proliferation and apoptosis (cell death) and has been implicated in a variety of diseases such as Alzheimer's disease.[29]

Pharmacokinetics

The pharmacokinetics of molecular hydrogen gas and hydrogen-rich saline require further research.[6] As of 2015, research on the effects of molecular hydrogen therapy in humans and other disease models is available[29] however, a more comprehensive understanding of pharmacokinetics, pharmacodynamics, biology and toxicity of hydrogen is needed.[3]

Research

Medical Use

Biomedical research on hydrogen is still in the development and existing publications suggest that molecular hydrogen has therapeutic potential.[8] Although the benefits of molecular hydrogen (H2) therapy involving animal models have been published, few clinical publications are available. In particular research is needed to clarify the difference between the effectiveness of inhalation, injection, and ingestion of molecular hydrogen for different diseases as well as optimal hydrogen dose.[30]

Cardiovascular Disease

Biomedical research on hydrogen is still in the development and existing publications suggest that molecular hydrogen has therapeutic potential.[8] Although the benefits of molecular hydrogen (H2) therapy involving animal models have been published, few clinical publications are available. In particular research is needed to clarify the difference between the effectiveness of inhalation, injection, and ingestion of molecular hydrogen for different diseases as well as optimal hydrogen dose.[30]

Allergic Reactions

In a 2009 mouse study,[31] it was demonstrated that consumption of hydrogen-rich water abolishes an immediate-type allergic reaction (Type-I allergy) by suppressing NADPH oxidase activity and therefore reducing the generation of hydrogen peroxide,[31] a type of ROS.[1] Here the benefits of molecular hydrogen therapy are not due to its radical scavenging properties but due to the modulation of a specific signalling pathway[31] changing the expression of pro-allergic proteins. Yet, this research still needs to be proven in a clinical setting.

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 Dixon, Brandon J; Tang, Jiping; Zhang, John H (2013). "The evolution of molecular hydrogen: A noteworthy potential therapy with clinical significance". Medical Gas Research. 3 (1): 10. doi:10.1186/2045-9912-3-10. PMC 3660246. PMID 23680032.
  2. ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 Ohsawa, Ikuroh; Ishikawa, Masahiro; Takahashi, Kumiko; Watanabe, Megumi; Nishimaki, Kiyomi; Yamagata, Kumi; Katsura, Ken-Ichiro; Katayama, Yasuo; Asoh, Sadamitsu; Ohta, Shigeo (2007). "Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals". Nature Medicine. 13 (6): 688–94. doi:10.1038/nm1577. PMID 17486089.
  3. ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 3.12 3.13 3.14 Huang, Chien-Sheng; Kawamura, Tomohiro; Toyoda, Yoshiya; Nakao, Atsunori (2010). "Recent advances in hydrogen research as a therapeutic medical gas". Free Radical Research. 44 (9): 971–82. doi:10.3109/10715762.2010.500328. PMID 20815764.
  4. ↑ 4.0 4.1 4.2 4.3 Lee, Mi Young; Kim, Yoon Kyoung; Ryoo, Kun Kul; Lee, Yoon Bae; Park, Eun Ju (2006). "Electrolyzed-Reduced Water Protects Against Oxidative Damage to DNA, RNA, and Protein". Applied Biochemistry and Biotechnology. 135 (2): 133–44. doi:10.1385/ABAB:135:2:133. PMID 17159237.
  5. ↑ 5.0 5.1 5.2 5.3 Iuchi, Katsuya; Imoto, Akemi; Kamimura, Naomi; Nishimaki, Kiyomi; Ichimiya, Harumi; Yokota, Takashi; Ohta, Shigeo (2016). "Molecular hydrogen regulates gene expression by modifying the free radical chain reaction-dependent generation of oxidized phospholipid mediators". Scientific Reports. 6: 18971. Bibcode:2016NatSR...618971I. doi:10.1038/srep18971. PMC 4704061. PMID 26739257.
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 6.6 Cai, Jianmei; Kang, Zhimin; Liu, Kan; Liu, Wenwu; Li, Runping; Zhang, John H.; Luo, Xu; Sun, Xuejun (2009). "Neuroprotective effects of hydrogen saline in neonatal hypoxia–ischemia rat model". Brain Research. 1256: 129–37. doi:10.1016/j.brainres.2008.11.048. PMID 19063869.
  7. ↑ Luo, Zhu-Lin; Cheng, Long; Ren, Jian-Dong; Fang, Chen; Xiang, Ke; Xu, Hao-Tong; Tang, Li-Jun; Wang, Tao; Tian, Fu-Zhou (2015). "Hydrogen-Rich Saline Protects against Ischemia/Reperfusion Injury in Grafts after Pancreas Transplantations by Reducing Oxidative Stress in Rats". Mediators of Inflammation. 2015: 281985. doi:10.1155/2015/281985. PMC 4385641. PMID 25873757.
  8. ↑ 8.0 8.1 8.2 8.3 "Hydrogen: an emerging medical gas". Molecular Hydrogen Foundation.
  9. ↑ Cai, Jianmei; Kang, Zhimin; Liu, Wen Wu; Luo, Xu; Qiang, Sun; Zhang, John H.; Ohta, Shigeo; Sun, Xuejun; Xu, Weigang; Tao, Hengyi; Li, Runping (2008). "Hydrogen therapy reduces apoptosis in neonatal hypoxia–ischemia rat model". Neuroscience Letters. 441 (2): 167–72. doi:10.1016/j.neulet.2008.05.077. PMID 18603371.
  10. ↑ 10.00 10.01 10.02 10.03 10.04 10.05 10.06 10.07 10.08 10.09 10.10 Nakao, Atsunori; Toyoda, Yoshiya; Sharma, Prachi; Evans, Malkanthi; Guthrie, Najla (2010). "Effectiveness of Hydrogen Rich Water on Antioxidant Status of Subjects with Potential Metabolic Syndrome—An Open Label Pilot Study". Journal of Clinical Biochemistry and Nutrition. 46 (2): 140–9. doi:10.3164/jcbn.09-100. PMC 2831093. PMID 20216947.
  11. ↑ 11.0 11.1 11.2 Kajiyama, Sizuo; Hasegawa, Goji; Asano, Mai; Hosoda, Hiroko; Fukui, Michiaki; Nakamura, Naoto; Kitawaki, Jo; Imai, Saeko; Nakano, Koji; Ohta, Mitsuhiro; Adachi, Tetsuo; Obayashi, Hiroshi; Yoshikawa, Toshikazu (2008). "Supplementation of hydrogen-rich water improves lipid and glucose metabolism in patients with type 2 diabetes or impaired glucose tolerance". Nutrition Research. 28 (3): 137–43. doi:10.1016/j.nutres.2008.01.008. PMID 19083400.
  12. ↑ 12.0 12.1 Sun, Hanyong; Chen, Lei; Zhou, Weiping; Hu, Liang; Li, Liang; Tu, Qianqian; Chang, Yanxin; Liu, Qu; Sun, Xuejun; Wu, Mengchao; Wang, Hongyang (2011). "The protective role of hydrogen-rich saline in experimental liver injury in mice". Journal of Hepatology. 54 (3): 471–80. doi:10.1016/j.jhep.2010.08.011. PMID 21145612.
  13. ↑ 13.0 13.1 Wang, Jie; Yi, Jing (2014). "Cancer cell killing via ROS: To increase or decrease, that is the question". Cancer Biology & Therapy. 7 (12): 1875–84. doi:10.4161/cbt.7.12.7067. PMID 18981733.
  14. ↑ 14.0 14.1 Jin, Qijiang; Zhu, Kaikai; Cui, Weiti; Xie, Yanjie; Han, BIN; Shen, Wenbiao (2013). "Hydrogen gas acts as a novel bioactive molecule in enhancing plant tolerance to paraquat-induced oxidative stress via the modulation of heme oxygenase-1 signalling system". Plant, Cell & Environment. 36 (5): 956–69. doi:10.1111/pce.12029. PMID 23094798.
  15. ↑ 15.0 15.1 15.2 Zhang, Yi; Su, Wen-Jun; Chen, Ying; Wu, Teng-Yun; Gong, Hong; Shen, Xiao-Liang; Wang, Yun-Xia; Sun, Xue-Jun; Jiang, Chun-Lei (2016). "Effects of hydrogen-rich water on depressive-like behavior in mice". Scientific Reports. 6: 23742. Bibcode:2016NatSR...623742Z. doi:10.1038/srep23742. PMC 4812321. PMID 27026206.
  16. ↑ Xu, Ying; Wang, Chuang; Klabnik, Jonathan; O' Donnell, James (2014). "Novel Therapeutic Targets in Depression and Anxiety: Antioxidants as a Candidate Treatment". Current Neuropharmacology. 12 (2): 108–19. doi:10.2174/1570159X11666131120231448. PMC 3964743. PMID 24669206.
  17. ↑ 17.0 17.1 Aoki, Kosuke; Nakao, Atsunori; Adachi, Takako; Matsui, Yasushi; Miyakawa, Shumpei (2012). "Pilot study: Effects of drinking hydrogen-rich water on muscle fatigue caused by acute exercise in elite athletes". Medical Gas Research. 2: 12. doi:10.1186/2045-9912-2-12. PMC 3395574. PMID 22520831.
  18. ↑ 18.0 18.1 Li, Jian; Wang, Cai; Zhang, John H.; Cai, Jian-Mei; Cao, Yun-Peng; Sun, Xue-Jun (2010). "Hydrogen-rich saline improves memory function in a rat model of amyloid-beta-induced Alzheimer's disease by reduction of oxidative stress". Brain Research. 1328: 152–61. doi:10.1016/j.brainres.2010.02.046. PMID 20171955.
  19. ↑ Klafki, H.-W.; Staufenbiel, M.; Kornhuber, J.; Wiltfang, J. (2006). "Therapeutic approaches to Alzheimer's disease". Brain. 129 (11): 2840–55. doi:10.1093/brain/awl280. PMID 17018549.
  20. ↑ 20.0 20.1 Guglielmotto, Michela; Tamagno, Elena; Danni, Oliviero (2009). "Oxidative Stress and Hypoxia Contribute to Alzheimer's Disease Pathogenesis: Two Sides of the Same Coin". The Scientific World Journal. 9: 781–91. doi:10.1100/tsw.2009.93. PMID 19705038.
  21. ↑ Schapira, Anthony HV (2008). "Mitochondria in the aetiology and pathogenesis of Parkinson's disease". The Lancet Neurology. 7 (1): 97–109. doi:10.1016/S1474-4422(07)70327-7. PMID 18093566.
  22. ↑ 22.0 22.1 Thomas, B.; Beal, M. F. (2007). "Parkinson's disease". Human Molecular Genetics. 16: R183–94. doi:10.1093/hmg/ddm159. PMID 17911161.
  23. ↑ 23.0 23.1 23.2 Yoritaka, Asako; Abe, Takashi; Ohtsuka, Chigumi; Maeda, Tetsuya; Hirayama, Masaaki; Watanabe, Hirohisa; Saiki, Hidemoto; Oyama, Genko; Fukae, Jiro; Shimo, Yasushi; Hatano, Taku; Kawajiri, Sumihiro; Okuma, Yasuyuki; Machida, Yutaka; Miwa, Hideto; Suzuki, Chikako; Kazama, Asuka; Tomiyama, Masahiko; Kihara, Takeshi; Hirasawa, Motoyuki; Shimura, Hideki; Hattori, Nobutaka (2016). "A randomized double-blind multi-center trial of hydrogen water for Parkinson's disease: Protocol and baseline characteristics". BMC Neurology. 16: 66. doi:10.1186/s12883-016-0589-0. PMC 4865993. PMID 27176725.
  24. ↑ 24.0 24.1 Fujita, Kyota; Seike, Toshihiro; Yutsudo, Noriko; Ohno, Mizuki; Yamada, Hidetaka; Yamaguchi, Hiroo; Sakumi, Kunihiko; Yamakawa, Yukiko; Kido, Mizuho A.; Takaki, Atsushi; Katafuchi, Toshihiko; Tanaka, Yoshinori; Nakabeppu, Yusaku; Noda, Mami (2009). "Hydrogen in Drinking Water Reduces Dopaminergic Neuronal Loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine Mouse Model of Parkinson's Disease". PLoS ONE. 4 (9): e7247. Bibcode:2009PLoSO...4.7247F. doi:10.1371/journal.pone.0007247. PMC 2747267. PMID 19789628.
  25. ↑ 25.0 25.1 Yoritaka, Asako; Takanashi, Masashi; Hirayama, Masaaki; Nakahara, Toshiki; Ohta, Shigeo; Hattori, Nobutaka (2013). "Pilot study of H2therapy in Parkinson's disease: A randomized double-blind placebo-controlled trial". Movement Disorders. 28 (6): 836–9. doi:10.1002/mds.25375. PMID 23400965.
  26. ↑ 26.0 26.1 Kato, Shinya; Saitoh, Yasukazu; Iwai, Keizou; Miwa, Nobuhiko (2012). "Hydrogen-rich electrolyzed warm water represses wrinkle formation against UVA ray together with type-I collagen production and oxidative-stress diminishment in fibroblasts and cell-injury prevention in keratinocytes". Journal of Photochemistry and Photobiology B: Biology. 106: 24–33. doi:10.1016/j.jphotobiol.2011.09.006. PMID 22070900.
  27. ↑ 27.0 27.1 Li, Yuping; Nishimura, T; Teruya, K; Maki, T; Komatsu, T; Hamasaki, T; Kashiwagi, T; Kabayama, S; Shim, S. Y.; Katakura, Y; Osada, K; Kawahara, T; Otsubo, K; Morisawa, S; Ishii, Y; Gadek, Z; Shirahata, S (2002). "Protective mechanism of reduced water against alloxan-induced pancreatic beta-cell damage: Scavenging effect against reactive oxygen species". Cytotechnology. 40 (1–3): 139–49. doi:10.1023/A:1023936421448. PMC 3449533. PMID 19003114.
  28. ↑ Koskimäki, Janne J; Kajula, Marena; Hokkanen, Juho; Ihantola, Emmi-Leena; Kim, Jong H; Hautajärvi, Heidi; Hankala, Elina; Suokas, Marko; Pohjanen, Johanna; Podolich, Olga; Kozyrovska, Natalia; Turpeinen, Ari; Pääkkönen, Mirva; Mattila, Sampo; Campbell, Bruce C; Pirttilä, Anna Maria (2016). "Methyl-esterified 3-hydroxybutyrate oligomers protect bacteria from hydroxyl radicals". Nature Chemical Biology. 12 (5): 332–8. doi:10.1038/nchembio.2043. PMID 26974813.
  29. ↑ 29.0 29.1 Klegeris, Andis; Walker, Douglas G; McGeer, Patrick L (1997). "Interaction of Alzheimer β-amyloid peptide with the human monocytic cell line THP-1 results in a protein kinase C-dependent secretion of tumor necrosis factor-α". Brain Research. 747 (1): 114–21. doi:10.1016/S0006-8993(96)01229-2. PMID 9042534.
  30. ↑ 30.0 30.1 Ichihara, Masatoshi; Sobue, Sayaka; Ito, Mikako; Ito, Masafumi; Hirayama, Masaaki; Ohno, Kinji (2015). "Beneficial biological effects and the underlying mechanisms of molecular hydrogen - comprehensive review of 321 original articles". Medical Gas Research. 5: 12. doi:10.1186/s13618-015-0035-1. PMC 4610055. PMID 26483953.
  31. ↑ 31.0 31.1 31.2 Itoh, Tomohiro; Fujita, Yasunori; Ito, Mikako; Masuda, Akio; Ohno, Kinji; Ichihara, Masatoshi; Kojima, Toshio; Nozawa, Yoshinori; Ito, Masafumi (2009). "Molecular hydrogen suppresses FcεRI-mediated signal transduction and prevents degranulation of mast cells". Biochemical and Biophysical Research Communications. 389 (4): 651–6. doi:10.1016/j.bbrc.2009.09.047. PMID 19766097.


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